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Metabolic constraint of human telomere length by nucleotide salvage efficiency

NATURE COMMUNICATIONS 2025年第1期16卷 1-14页

作者： Mannherz, William Crompton, Andrew Lampl, Noah Agarwal, Suneet Boston Childrens Hosp Oncol & Stem Cell Program Div Hematol Boston MA 02115 USA Dana Farber Canc Inst Pediat Oncol Boston MA 02215 USA Harvard Med Sch Harvard Stem Cell Inst Dept Pediat Harvard Initiat RNA Med Boston MA 02215 USA Harvard Med Sch Biol & Biomed Sci PhD Program Biol & Biomed Sci PhD Program Boston MA 02215 USA Harvard Med Sch Harvard MIT MD PhD Program Boston MA 02215 USA

Human telomere length is tightly regulated and associated with diseases at either extreme, but how these bounds are established remains incompletely understood. Here, we developed a rapid cell-based telomere synthesis assay and found that nucleoside salvage bidirectionally constrains human telomere length. Metabolism of deoxyguanosine (dG) or guanosine via purine nucleoside phosphorylase (PNP) and hypoxanthine-guanine phosphoribosyltransferase to form guanine ribonucleotides strongly inhibited telomerase and shortened telomeres. Conversely, salvage of dG to its nucleotide forms via deoxycytidine kinase drove potent telomerase activation, the extent of which was controlled by the dNTPase SAMHD1. Circumventing limits on salvage by expressing Drosophila melanogaster deoxynucleoside kinase or augmenting dG metabolism using the PNP inhibitor ulodesine robustly lengthened telomeres in human cells, including those from patients with lethal telomere diseases. Our results provide an updated paradigm for telomere length control, wherein telomerase reverse transcriptase activity is actively and bidirectionally constrained by the availability of its dNTP substrates, in a manner that may be therapeutically actionable.

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SLC25A38 is required for mitochondrial pyridoxal 5'-phosphate (PLP) accumulation

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NATURE COMMUNICATIONS 2025年第1期16卷 1-19页

作者： Pena, Izabella A. Shi, Jeffrey S. Chang, Sarah M. Yang, Jason Block, Samuel Adelmann, Charles H. Keys, Heather R. Ge, Preston Bathla, Shveta Witham, Isabella H. Sienski, Grzegorz Nairn, Angus C. Sabatini, David M. Lewis, Caroline A. Kory, Nora Vander Heiden, Matthew G. Heiman, Myriam MIT Picower Inst Learning & Memory Cambridge MA 02139 USA MIT Dept Brain & Cognit Sci Cambridge MA 02139 USA MIT Dept Biol Cambridge MA USA MIT David H Koch Inst Integrat Canc Res Cambridge MA USA Harvard MIT MD PhD Program Boston MA USA Whitehead Inst Biomed Res Cambridge MA USA Massachusetts Gen Hosp Ctr Canc Res Boston MA USA Harvard Med Sch Massachusetts Gen Hosp Cutaneous Biol Res Ctr Dept Dermatol Boston MA USA Yale Sch Med Dept Psychiat New Haven CT USA MIT Dept Biol Engn Cambridge MA USA Inst Organ Chem & Biochem IOCB Prague Czech Republic UMass Chan Med Sch Program Mol Med Worcester MA USA Harvard TH Chan Sch Publ Hlth Boston MA USA Dana Farber Canc Inst Boston MA USA Childrens Hosp Eastern Ontario CHEO Res Inst Ottawa ON Canada

Many essential proteins require pyridoxal 5'-phosphate, the active form of vitamin B6, as a cofactor for their activity. These include enzymes important for amino acid metabolism, one-carbon metabolism, polyamine synthesis, erythropoiesis, and neurotransmitter metabolism. A third of all mammalian pyridoxal 5'-phosphate-dependent enzymes are localized in the mitochondria;however, the molecular machinery involved in the regulation of mitochondrial pyridoxal 5'-phosphate levels in mammals remains unknown. In this study, we used a genome-wide CRISPR interference screen in erythroleukemia cells and organellar metabolomics to identify the mitochondrial inner membrane protein SLC25A38 as a regulator of mitochondrial pyridoxal 5'-phosphate. Loss of SLC25A38 causes depletion of mitochondrial, but not cellular, pyridoxal 5'-phosphate, and impairs cellular proliferation under both physiological and low vitamin B6 conditions. Metabolic changes associated with SLC25A38 loss suggest impaired mitochondrial pyridoxal 5'-phosphate-dependent enzymatic reactions, including serine to glycine conversion catalyzed by serine hydroxymethyltransferase-2 as well as ornithine aminotransferase. The proliferation defect of SLC25A38-null K562 cells in physiological and low vitamin B6 media can be explained by the loss of serine hydroxymethyltransferase-2-dependent production of one-carbon units and downstream de novo nucleotide synthesis. Our work points to a role for SLC25A38 in mitochondrial pyridoxal 5'-phosphate accumulation and provides insights into the pathology of congenital sideroblastic anemia.

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Probabilistic genotype-phenotype maps reveal mutational robustness of RNA folding, spin glasses, and quantum circuits

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Physical Review Research 2025年第1期7卷 013118-013118页

作者： Anna Sappington Vaibhav Mohanty Department of Electrical Engineering and Computer Science Massachusetts Institute of Technology Cambridge Massachusetts 02139 USA Harvard-MIT Program in Health Sciences and Technology Harvard Medical School Boston Massachusetts 02115 USA and Massachusetts Institute of Technology Cambridge Massachusetts 02139 USA Harvard/MIT MD-PhD Program Harvard Medical School Boston Massachusetts 02115 USA and Massachusetts Institute of Technology Cambridge Massachusetts 02139 USA Department of Chemistry and Chemical Biology Harvard University Cambridge Massachusetts 02138 USA

Recent studies of genotype-phenotype maps have reported universally enhanced phenotypic robustness to genotype mutations, a feature essential to evolution. Virtually all of these studies make a simplifying assumption that each genotype—represented as a sequence—maps deterministically to a single phenotype, such as a discrete structure. Here we introduce probabilistic genotype-phenotype (PrGP) maps, where each genotype maps to a vector of phenotype probabilities, as a more realistic and universal language for investigating robustness in a variety of physical, biological, and computational systems. We study three model systems to show that PrGP maps offer a generalized framework which can handle uncertainty emerging from various physical sources: (1) thermal fluctuation in RNA folding, (2) external field disorder in the spin-glass ground state search problem, and (3) superposition and entanglement in quantum circuits, which are realized experimentally on IBM quantum computers. In all three cases, we observe a biphasic robustness scaling which is enhanced relative to random expectation for more frequent phenotypes and approaches random expectation for less frequent phenotypes. We derive an analytical theory for the behavior of PrGP robustness, and we demonstrate that the theory is highly predictive of empirical robustness.

关键词： Quantum computers

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Genomic data processing with GenomeFlow

arXiv

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arXiv 2025年

作者： Park, Junseok Maury, Eduardo A. Oh, Changhoon Shin, Donghoon Denisko, Danielle Lee, Eunjung Alice Division of Genetics and Genomics Boston Children’s Hospital 3 Blackfan Circle BostonMA United States Department of Pediatrics Harvard Medical School 25 Shattuck St BostonMA United States Bioinformatics Integrative Genomics Program Harvard/MIT MD-PHD Program Harvard Medical School BostonMA United States Program in Medical and Population Genetics Broad Institute of MIT and Harvard CambridgeMA United States Graduate School of Information Yonsei University 50 Yonsei-ro Seodaemun-gu Seoul Korea Republic of Department of Human Centered Design and Engineering University of Washington SeattleWA United States Department of Biomedical Informatics Harvard Medical School BostonMA United States

Advances in genome sequencing technologies generate massive amounts of sequence data that are increasingly analyzed and shared through public repositories. On-demand infrastructure services on cloud computing platforms enable the processing of such large-scale genomic sequence data in distributed processing environments with a significant reduction in analysis time. However, parallel processing on cloud computing platforms presents many challenges to researchers, even skillful bioinformaticians. In particular, it is difficult to design a computing architecture optimized to reduce the cost of computing and disk storage as genomic data analysis pipelines often employ many heterogeneous tools with different resource requirements. To address these issues, we developed GenomeFlow, a tool for automated development of computing architecture and resource optimization on Google Cloud Platform, which allows users to process a large number of samples at minimal cost. We outline multiple use cases of GenomeFlow demonstrating its utility to significantly reduce computing time and cost associated with analyzing genomic and transcriptomic data from hundreds to tens of thousands of samples from several consortia. Here, we describe a step-by-step protocol on how to use GenomeFlow for a common genomic data processing task. We introduce this example protocol geared toward a bioinformatician with little experience in cloud computing. © 2025, CC BY.

关键词： Cloud platforms

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Accounting for future populations in health research

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BIOETHICS 2024年第5期38卷 401-409页

作者： Pierson, Leah Harvard Med Sch Harvard MIT MD PhD Program Boston MA 02115 USA Harvard TH Chan Sch Publ Hlth Dept Global Hlth & Populat Boston MA USA

The research we fund today will improve the health of people who will live tomorrow. But future people will not all benefit equally: decisions we make about what research to prioritize will predictably affect when and how much different people benefit from research. Organizations that fund health research should thus fairly account for the health needs of future populations when setting priorities. To this end, some research funders aim to allocate research resources in accordance with disease burden, prioritizing illnesses that cause more morbidity and mortality. In this article, I defend research funders' practice of aligning research funding with disease burden but argue that funders should aim to align research funding with future-rather than present-disease burden. I suggest that research funders should allocate research funding in proportion to aggregated estimates of disease burden over the period when research could plausibly start to yield benefits until indefinitely into the future.

关键词： disease burden health policy longtermism priority setting resource allocation

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Protein-based nanoparticles for therapeutic nucleic acid delivery

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BIOMATERIALS 2024年 305卷 122464-122464页

作者： Eweje, Feyisayo Walsh, Michelle L. Ahmad, Kiran Ibrahim, Vanessa Alrefai, Assma Chen, Jiaxuan Chaikof, Elliot L. Harvard Med Sch Beth Israel Deaconess Med Ctr Dept Surg Boston MA 02215 USA MIT Harvard & MIT Div Hlth Sci & Technol Cambridge MA 02139 USA Harvard MIT MD PhD Program Boston MA 02115 USA Harvard Univ Wyss Inst Biol Inspired Engn Boston MA 02115 USA

To realize the full potential of emerging nucleic acid therapies, there is a need for effective delivery agents to transport cargo to cells of interest. Protein materials exhibit several unique properties, including biodegradability, biocompatibility, ease of functionalization via recombinant and chemical modifications, among other features, which establish a promising basis for therapeutic nucleic acid delivery systems. In this review, we highlight progress made in the use of non-viral protein-based nanoparticles for nucleic acid delivery in vitro and in vivo, while elaborating on key physicochemical properties that have enabled the use of these materials for nanoparticle formulation and drug delivery. To conclude, we comment on the prospects and unresolved challenges associated with the translation of protein-based nucleic acid delivery systems for therapeutic applications.

关键词： Drug delivery Gene therapy Recombinant proteins Nanoparticles Polypeptides

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Postoperative Pathway Allows Elective Craniotomy Patients to Bypass Intensive Care Unit Safely: Commentary on Recent Article in Journal of Neurosurgery

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WORLD NEUROSURGERY 2023年 173卷 276-277页

作者： Hoffman, Samantha E. Gupta, Saksham Arnaout, Omar Brigham & Womens Hosp Dept Neurosurg Boston MA 02115 USA Harvard Med Sch Harvard MIT MD PhD Program Boston MA 02115 USA

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A viable alternative for editor delivery

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BLOOD 2023年第9期142卷 755-756页

作者： Eweje, Feyisayo Bauer, Daniel E. MIT Cambridge MA 02142 USA Harvard MIT MD PhD Program Cambridge MA 02115 USA Boston Childrens Hosp Boston MA USA Harvard Med Sch Boston MA USA

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βIV spectrin abundancy, cellular distribution and sensitivity to AKT/GSK3 regulation in schizophrenia

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MOLECULAR PSYCHIATRY 2025年 1-13页

作者： Di Re, Jessica Marini, Michela Hussain, Syed Ibrar Singh, Aditya K. Venkatesh, Akshaya Alshammari, Musaad A. Alshammari, Tahani K. Hamoud, Abdul-Rizaq Ali Imami, Ali Sajid Haghighijoo, Zahra Fularcyzk, Nickolas Stertz, Laura Hawes, Derek Mosebarger, Angela Jernigan, Jordan Chaljub, Claire Nehme, Ralda Walss-Bass, Consuelo Schulmann, Anton Vawter, Marquis P. Mccullumsmith, Robert Damoiseaux, Robert D. Limon, Agenor Labate, Demetrio Wells, Michael F. Laezza, Fernanda Univ Texas Med Branch Galveston Dept Pharmacol & Toxicol Galveston TX USA Univ Houston Dept Math Houston TX USA Univ Texas Med Branch Combined MD PhD Program Galveston TX USA King Saud Univ Coll Pharm Dept Pharmacol & Toxicol Riyadh 11451 Saudi Arabia Univ Toledo Coll Med & Life Sci Dept Neurosci & Psychiat Toledo OH USA Univ Texas Hlth Sci Ctr Houston UTHealth McGovern Med Sch Louis A Faillace MD Dept Psychiat & Behav Sci Houston TX USA Broad Inst MIT & Harvard Stanley Ctr Psychiat Res Cambridge MA 02142 USA Harvard Univ Dept Stem Cell & Regenerat Biol Cambridge MA USA Columbia Univ Irving Med Ctr New York State Psychiat Inst Dept Psychiat New York NY USA Univ Calif Irvine Dept Psychiat & Human Behav Funct Genom Lab Irvine CA USA Promedica Neurosci Inst Toledo OH USA Univ Calif Los Angeles Dept Mol & Med Pharmacol Los Angeles CA USA Univ Calif Los Angeles Dept Bioengn Los Angeles CA USA Univ Calif Los Angeles Calif NanoSyst Inst Los Angeles CA USA Univ Calif Los Angeles Jonsson Comprehens Canc Ctr Los Angeles CA USA Univ Texas Med Branch Galveston Dept Neurol Galveston TX USA Univ Texas Med Branch Galveston Mitchell Ctr Neurodegenerat Dis Galveston TX USA Univ Calif Los Angeles David Geffen Sch Med Dept Human Genet Los Angeles CA USA Univ Calif Los Angeles Mol Biol Inst Los Angeles CA USA

Schizophrenia (SCZ) is a complex psychiatric disorder with unclear biological mechanisms. Spectrins, cytoskeletal proteins linked to neurodevelopmental disorders, are regulated by the AKT/GSK3 pathway, which is implicated in SCZ. However, the impact of SCZ-related dysregulation of this pathway on spectrin expression and distribution remains unexplored. Here, we show that beta IV spectrin protein levels were reduced in neurons of the dorsolateral prefrontal cortex in SCZ postmortem samples compared to healthy control (HC) from the Human Brain Collection Core (HBCC). To investigate potential links between beta IV spectrin and the AKT/GSK3 pathway, we analyzed the PsychEncode dataset, revealing elevated SPTBN4 and AKT2 mRNA levels with correlated gene transcription in both HCs and individuals with SCZ. Next, computational tools were employed to identify potential AKT and GSK3 phosphorylation sites on beta IV spectrin, and two GSK3 sites were validated through in vitro assays. To assess whether beta IV spectrin distribution and sensitivity to AKT/GSK3 are altered in SCZ, we used iPSC-derived neurons from two independent cohorts of patients with significantly increased familial genetic risk for the disorder. Alteration in beta IV spectrin levels and sensitivity to AKT/GSK3 inhibitors were consistently observed across both cohorts. Importantly, a Random Forest classifier applied to beta IV spectrin imaging achieved up to 98% accuracy in classifying cells by diagnosis in postmortem samples, and by diagnosis or diagnosis x perturbation in iPSC samples. These findings reveal altered beta IV spectrin levels and AKT/GSK3 sensitivity in SCZ, identifying beta IV spectrin image-based endophenotypes as robust, generalizable predictive biomarkers of SCZ, with the potential for scalable clinical applications.

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Clinical Applications of Naturally Derived Biopolymer-Based Scaffolds for Regenerative Medicine (vol 43, pg 657, 2014)

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ANNALS OF BIOMEDICAL ENGINEERING 2015年第8期43卷 2023-2023页

作者： Stoppel, Whitney L. Ghezzi, Chiara E. McNamara, Stephanie L. Black, Lauren D., III Kaplan, David L. Tufts Univ Dept Biomed Engn Medford MA 02155 USA Tufts Univ Sackler Sch Grad Biomed Sci Sch Med Cellular Mol & Dev Biol Program Boston MA 02111 USA Harvard Univ Sch Med Harvard MIT MD PhD Program Boston MA 02115 USA

Naturally derived polymeric biomaterials, such as collagens, silks, elastins, alginates, and fibrins are utilized in tissue engineering due to their biocompatibility, bioactivity, and tunable mechanical and degradation kinetics. The use of these natural biopolymers in biomedical applications is advantageous because they do not release cytotoxic degradation products, are often processed using environmentally-friendly aqueous-based methods, and their degradation rates within biological systems can be manipulated by modifying the starting formulation or processing conditions. For these reasons, many recent in vivo investigations and FDA-approval of new biomaterials for clinical use have utilized natural biopolymers as matrices for cell delivery and as scaffolds for cell-free support of native tissues. This review highlights biopolymer-based scaffolds used in clinical applications for the regeneration and repair of native tissues, with a focus on bone, skeletal muscle, peripheral nerve, cardiac muscle, and cornea substitutes.

关键词： Biopolymers Regenerative medicine Scaffolds

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